11-45910147-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BS1_Supporting

The ENST00000241041.7(PEX16):c.983C>T(p.Pro328Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,611,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: PEX16 ENST00000241041.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.23

Genes affected

PEX16 (HGNC:8857): (peroxisomal biogenesis factor 16) The protein encoded by this gene is an integral peroxisomal membrane protein. An inactivating nonsense mutation localized to this gene was observed in a patient with Zellweger syndrome of the complementation group CGD/CG9. Expression of this gene product morphologically and biochemically restores the formation of new peroxisomes, suggesting a role in peroxisome organization and biogenesis. Alternative splicing has been observed for this gene and two variants have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a region_of_interest Interaction with PEX19 (size 115) in uniprot entity PEX16_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in ENST00000241041.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010668039).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000328 (50/152322) while in subpopulation AMR AF= 0.000784 (12/15306). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX16	NM_004813.4	c.*107C>T		3_prime_UTR_variant	11/11	ENST00000378750.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX16	ENST00000241041.7	c.983C>T	p.Pro328Leu	missense_variant	11/11	1
PEX16	ENST00000378750.10	c.*107C>T		3_prime_UTR_variant	11/11	1	NM_004813.4	P1
PEX16	ENST00000523721.2			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000208 AC: 52 AN: 250180 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135492

Gnomad AFR exome AF: 0.000742

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000273 AC: 398 AN: 1459592 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 186 AN XY: 726082

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74500

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000559

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 8A (Zellweger) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.060
Dann	Benign	0.77
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.029
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.038	D
Polyphen		0.0	B
Vest4		0.081
MVP		0.048
MPC		1.1
ClinPred		0.066	T
GERP RS		-10
gMVP		0.58

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201513691; hg19: chr11-45931698;